1. Field of the Invention
This invention relates to the use of the compounds of benzofuroxan series in therapeutics. In particular the invention concerns pharmaceutical compositions containing benzofuroxan derivatives as active ingredients and their use as tolerance resistant nitric oxide donors in treatment of angina pectoris.
2. Description of the Prior Art
After the discovery of endothelium-derived relaxing factor (EDRF) by Furchgott et al (1980), and the elucidation of the biochemistry of EDRF by a number of laboratories (Ignarro, 1989; Vane et al, 1990, Bassenge et al, 1988; and Vanhoutte, 1989) it is now widely accepted that EDRF is the endogenous nitrovasodilator, nitric oxide (NO) donor. The organic nitrates and related compounds owe their pharmacological action to the release of nitric oxide (NO) and these compounds are collectively called nitrovasodilators. NO stimulates the guanylate cyclase enzyme in vascular smooth muscle cells resulting in increased levels of cyclic GMP. This leads to dephosphorylation of myosin light chain which results in relaxation of smooth muscles (Murad 1986). NO is known to be involved in a number of bio-regulatory processes like, vasodilatation, platelet deaggregation, vascular smooth muscle proliferation, etc.
Organic nitrates are used in prophylaxis, treatment and management of patients with angina pectoris. These are also useful in congestive heart failure associated with acute myocardial infarction, hypertension associated with surgical procedures and to produce controlled hypotension during surgical procedures. Among organic nitrates, nitroglycerine (sublingual) which is currently in use, is the drug of choice for immediate relief of anginal symptoms. Prophylactic treatment of stable angina pectoris involves the use of one or more drugs such as long acting nitrates like isosorbide dinitrate, a beta-blocker and/or a calcium channel antagonist, particularly in patients likely to experience coronary spasm. In some cases this triple therapy satisfactorily control angina. They are quite effective in the treatment of these conditions when used intermittently.
Frequently repeated use of nitrates result in decrease in their pharmacological effects, a phenomenon well recognized as nitrate tolerance. The mechanism of tolerance is not well defined As early as 1973, Needleman and Johnson (1973) have reported that tolerance to nitroglycerine could occur in isolated rabbit arteries. It was hypothesized by them that depletion of sulphydryl groups was associated with the development of tolerance to nitroglycerine. This is a major problem in the clinical use of organic nitrates (Frampton et al, 1992). Currently, the development of tolerance is reduced by the use of intermittent dosing schedule with a nitrate-free interval of 10-12 hrs. However, this intermittent use is associated with decreased exercise tolerance during the last part of nitrate-free interval. This suggests possibility of increased frequency of or severity of angina during nitrate-free interval. The importance of development of tolerance has increased as these drugs are used more commonly in various dosage forms like oral, transdermal, and intravenous preparations and even as sustained-release preparations. Several indirect indices like exercise duration, systemic blood pressure, pulmonary artery pressures and pulmonary artery wedge pressure has been used to assess tolerance to organic nitrates. However, it is not clear whether decreased response to nitrates is due to tolerance of the vascular smooth muscle cells or changes in regulatory factors like activation of neurohumoral factors or fluid retention etc. (Armstrong and Moffat, 1983). Irrespective of the mechanisms of tolerance development, clinically it is important to develop nitric oxide donors with least tendency to develop tolerance.
This problem of "tolerance" is still confronting the physicians as is be evident from
(a) The Merck Manual of diagnosis and therapy (16th Edition 1992), pages 498-505, PA0 (b) MARTINDALE, The Extra Pharmacopoea (30th Edition) 1993, pages 1019-1021, PA0 (c) The Essential Guide to Prescription Drugs 1994 edited by James W Long and James J Rybacki, pages 42-46, (d) Harrison's Principles of Internal Medicine (13th Edition 1944) page 1077-1084 and (e) Goodman and Gilman's, The Pharmacological Basis of Therapeutics (9th edition, 1996) pages 759-767.
P B Ghosh et al. (Journal of Medicinal Chemistry, 1968) disclosed the method of synthesis of various benzo-2,1,3-oxadiazoles (benzofurazans) and their N-oxides (benzofuroxans) and their potential as antileukemic and immuno-suppressive drugs in vitro.
P B Ghosh et al. (Journal of Medicinal Chemistry, 1972) tested 4-nitro benzofurazans and 4-nitrobenzofuroxans bearing electron withdrawing substitutents in the 5 and 6 position (relative to NO.sub.2) as potential antileukemic and immuno suppressive drugs in vitro.
P B Ghosh et al (Journal of Medicinal Chemistry, 1974) tested benzofuroxan and its derivatives for their vasodilation activities and found flurazanobenzofuroxan, furazobenzothiadiazole and their N-oxides as potent vasodilators.
Nishikawa et al. (The Journal of Pharmacology and Experimental Therapeutics, 1982) disclosed effect of N-ethoxycarbonyl-3-morpholinosydnonimine and its metabolites 3-morpholinosydnonimine, cyanomethyleneamino morpholine, N-nitroso-N-morpholinoamino acetonitrile as novel antianginal agent.
F. Murad (J. Clin. Invest, 1986) disclosed cyclic guanosine monophosphate as a mediator of vasodilation.
James Frampton et al. (Drug Evaluation, Adis International Limited, 1992) gives a review of pharmacology and therapeutic efficiency of nicorandil in angina pectoris. Nicorandil, which has both vasodilator and venodilating properties was found to offer an effective alternative to established vasodilator therapy with conventional nitrates and calcium antagonists in the long term treatment of stable angina pectoris.
U.S. Pat. No. 5,272,164 disclosed novel carboximidamide derivatives particularly N-cyano-N.sup.1 -substituted pyridine carboximidamide derivatives having vasodilating effect and hypotensive effect besides other physiological effects which are helpful in treatment of ischemic heart diseases.
U.S. Pat. No. 5,424,326 disclosed phenyl-1,2,5-oxadiazole carboxamide-2-oxide and its derivatives, which are useful for the treatment of disorders of the cardiovascular system.
EP-A-0 574726 disclosed fused 1,2,5-ozadiazole-2-oxides i.e. furoxan derivatives their preparation and use as pharmaceutically active compounds including pharmaceutical compositions for treatment of angina pectoris.
F Benedini et. al. (J. Med. Chem. 1995) disclosed a new nitro ester-3-[(nitroxy)alkyl]-2H-1,3-benzoxazin-4(3H)-ones showing marked inhibitory activity against ischemia-induced electrocardiographic changes, with only limited systemic hemodynamic effects. These new nitro ester derivatives, endowed with marked anti-anginal activity, which is not associated with concurrent and pronounced fall in systemic blood pressure, are indicative of a new class of selective nitrovasodilators having a preferential action on large coronary vessels, which could be clinically relevant in the treatment of coronary artery diseases.
However, none of the above prior art disclosures on the drugs specifically used as vasodilator for treatment of cardiac ailments tackles the problem associated with the conventional NO-donors to develop tolerance in the patient after continuous use for a period of time. The present invention evaluates the benzofuroxan derivatives for their NO donor activities particularly with reference to their tendency to develop tolerance for continued application of the drug. Significantly, the invention identifies the molecules showing vasodilator activity without tendency to develop tolerance unlike the conventional nitric-oxide donors.